Royal jelly (RJ) is a gelatinous secretion from young nurse worker bees (Apis mellifera), which serves as the sole food for the queen bee. Because of its pleiotropic functions for queen bees, RJ has also been used as a dietary supplement with various health benefits for humans. Because RJ is being indicated to have immunomodulatory potential for humans, we undertook the study to determine whether the oral administration of RJ could alter the development of systemic autoimmunity in New Zealand Black (NZB) x New Zealand White (NZW) F1 mice that genetically exhibit many manifestations similar to human systemic lupus erythematosus (SLE). We herein reported that mice administered with RJ showed a significant delay in the onset of the disease, as manifested by decreased proteinuria and a prolongation of lifespan. In addition, RJ administration after the onset of the disease significantly improved the renal symptoms, leading to an extended lifespan. RJ administration to mice caused a significant decrease in the serum level of IL-10, and in the autoantibodies against ssDNA, dsDNA and erythrocytes, as well as a reduction in the number of splenic autoreactive B cells. In conclusion, our data suggest that the use of RJ may be beneficial in the prevention of the early onset of SLE and in the control of the active progression of the manifestations of SLE.